The Rate of Vitamin A Dimerization in Lipofuscinogenesis, Fundus Autofluorescence, Retinal Senescence and Degeneration

Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 854)

Abstract

One of the earliest events preceding several forms of retinal degeneration is the formation and accumulation of vitamin A dimers in the retinal pigment epithelium (RPE) and underlying Bruch’s membrane (BM). Such degenerations include Stargardt disease, Best disease, forms of retinitis pigmentosa, and age-related macular degeneration (AMD). Since their discovery in the 1990’s, dimers of vitamin A, have been postulated as chemical triggers driving retinal senescence and degeneration. There is evidence to suggest that the rate at which vitamin A dimerizes and the eye’s response to the dimerization products may dictate the retina’s lifespan. Here, we present outstanding questions, finding the answers to which may help to elucidate the role of vitamin A dimerization in retinal degeneration.

Keywords

Stargardt Age-related macular degeneration AMD ABCA4 RPE Vitamin A Retinaldehyde Bisretinoids Vitamin A dimer A2E Lipofuscin Fundus autofluorescence Visual cycle 

References

  1. Bhosale P, Serban B, Bernstein PS (2009) Retinal carotenoids can attenuate formation of A2E in the retinal pigment epithelium. Arch Biochem Biophys 483:175–181CrossRefPubMedPubMedCentralGoogle Scholar
  2. Brogan AP, Dickerson TJ, Boldt GE et al (2005) Altered retinoid homeostasis catalyzed by a nicotine metabolite: implications in macular degeneration and normal development. Proc Natl Acad Sci U S A 102:10433–10438CrossRefPubMedPubMedCentralGoogle Scholar
  3. Charbel Issa P, Barnard A, Herrmann P et al (2015) Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization. Proc Natl Acad Sci doi: 10.1073/pnas.1506960112Google Scholar
  4. Dontsov AE, Koromyslova AD, Sakina NL (2013) Lipofuscin component A2E does not reduce antioxidant activity of DOPA-melanin. Bull Exp Biol Med 154:624–627CrossRefPubMedGoogle Scholar
  5. Eldred GE (1993) Retinoid reaction products in age related retinal degeneration. In: Hollyfield JG, Anderson RE, LaVail MM (eds) Retinal degeneration: clinical and laboratory applications. Plenum, New York, pp 15–24CrossRefGoogle Scholar
  6. Finnemann S, Leung LW, Rodriguez-Boulan E (2002) The lipofuscin component A2E selectively inhibits phagolysosomal degradation of photoreceptor phospholipid by the retinal pigment epithelium. Proc Natl Acad Sci U S A 99:3842–3847CrossRefPubMedPubMedCentralGoogle Scholar
  7. Fishkin N, Jang YP, Itagaki Y et al (2003) A2-rhodopsin: a new fluorophore isolated from photoreceptor outer segments. Org Biomol Chem 1:1101–1105CrossRefPubMedGoogle Scholar
  8. Iriyama A, Fujiki R, Inoue Y et al (2008) A2E, a pigment of the lipofuscin of retinal pigment epithelial cells, is an endogenous ligand for retinoic acid receptor. J Biol Chem 283:11947–11953CrossRefPubMedGoogle Scholar
  9. Kaufman Y, Ma L, Washington I (2011) Deuterium enrichment of vitamin A at the C20 position slows the formation of detrimental vitamin A dimers in wild-type rodents. J Biol Chem 286:7958–7965CrossRefPubMedPubMedCentralGoogle Scholar
  10. Lukiw WJ, Mukherjee PK, Cui JG et al (2006) A2E selectively induces cox-2 in ARPE-19 and human neural cells. Curr Eye Res 31:259–263CrossRefPubMedGoogle Scholar
  11. Ma L, Kaufman Y, Zhang J et al (2011) C20-D3-vitamin A slows lipofuscin accumulation and electrophysiological retinal degeneration in a mouse model of Stargardt disease. J Biol Chem 286:7966–7974CrossRefPubMedPubMedCentralGoogle Scholar
  12. Maeda A, Maeda T, Golczak M et al (2009) Involvement of all-trans-retinal in acute light-induced retinopathy of mice. J Biol Chem 284:15173–15183CrossRefPubMedPubMedCentralGoogle Scholar
  13. Mihai DM, Washington I (2014) Vitamin A dimers trigger the protracted death of retinal pigment epithelium cells. Cell Death Dis 5:e1348CrossRefPubMedPubMedCentralGoogle Scholar
  14. Moiseyev G, Nikolaeva O, Chen Y et al (2010) Inhibition of the visual cycle by A2E through direct interaction with RPE65 and implications in Stargardt disease. Proc Natl Acad Sci U S A 107:17551–17556CrossRefPubMedPubMedCentralGoogle Scholar
  15. Murdaugh LS, Wang Z, Del Priore LV et al (2010) Age-related accumulation of 3-nitrotyrosine and nitro-A2E in human Bruch’s membrane. Exp Eye Res 90:564–571CrossRefPubMedGoogle Scholar
  16. Penn J, Mihai DM, Washington I (2014) Morphologic and physiologic retinal degeneration induced by intravenous delivery of vitamin A dimers in the leporid retina. Dis Model Mech 8:131–8Google Scholar
  17. Radu RA, Hu J, Jiang Z et al (2014) Bisretinoid-mediated complement activation on retinal pigment epithelial cells is dependent on complement factor H haplotype. J Biol Chem 289:9113–9120CrossRefPubMedPubMedCentralGoogle Scholar
  18. Sparrow JR, Boulton M (2005) RPE lipofuscin and its role in retinal pathobiology. Exp Eye Res 80:595–606CrossRefPubMedGoogle Scholar
  19. Sparrow JR, Gregory-Roberts E, Yamamoto K et al (2012) The bisretinoids of retinal pigment epithelium. Prog Retin Eye Res 31:121–135CrossRefPubMedPubMedCentralGoogle Scholar
  20. Sparrow JR, Fishkin N, Zhou J et al (2003) A2E, a byproduct of the visual cycle. Vision Res 43:2983–2990CrossRefPubMedGoogle Scholar
  21. Thao MT, Renfus DJ, Dillon J et al (2014) A2E-mediated photochemical modification to fibronectin and its implications to age-related changes in Bruch’s membrane. Photochem Photobiol 90:329–334CrossRefPubMedGoogle Scholar
  22. Washington I, Jockusch S, Itagaki Y et al (2005) Superoxidation of bisretinoids. Angew Chem Int Ed Engl 44:7097–7100CrossRefPubMedGoogle Scholar
  23. Washington I, Turro NJ, Nakanishi K (2006) Superoxidation of retinoic acid. Photochem Photobiol 82:1394–1397PubMedGoogle Scholar
  24. Yoon KD, Yamamoto K, Ueda K et al (2012) A novel source of methylglyoxal and glyoxal in retina: implications for age-related macular degeneration. PLoS One 7:e41309CrossRefPubMedPubMedCentralGoogle Scholar
  25. Zhou J, Jang YP, Kim SR et al (2006) Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium. Proc Natl Acad Sci 103:16182–7Google Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of OphthalmologyColumbia University Medical CenterNew YorkUSA
  2. 2.Alkeus Pharmaceuticals, Inc.BostonUSA

Personalised recommendations